研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Generation of pluripotent stem cells from neonatal mouse testis

Kanatsu-Shinohara M, Inoue K, Lee J, Yoshimoto M, Ogonuki N, Miki H, Baba S, Kato T, Kazuki Y, Toyokuni S, Toyoshima M, Niwa O, Oshimura M, Heike T, Nakahata T, Ishino F, Ogura A, Shinohara T

CELL 119 巻 ( 7 ) 頁： 1001 - 1012 2004年12月

オキシカインによる糖尿病性腎症の進展抑制効果査読有り

市川寛, 赤桐里美, 内藤裕二, 内山和彦, 吉田憲正, 豊國伸哉, 吉川敏一

日本病態栄養学会誌 7 巻 ( 4 ) 頁： 375 - 375 2004年11月

Novel mechanism of matrix metalloproteinase inhibitor in the treatment of heart failure:: Direct inhibition of myocardial oxidant stress and NF-κB activation in rats

Takenaka, H; Kihara, Y; Iwanaga, Y; Onozawa, Y; Toyokuni, S; Kita, T

CIRCULATION 110 巻 ( 17 ) 頁： 514 - 515 2004年10月

Novel mechanism of matrix metalloproteinase inhibitor in the treatment of heart failure: Direct inhibition of myocardial oxidant stress and NF-kappa B activation in rats 国際誌

Takenaka H, Kihara Y, Iwanaga Y, Onozawa Y, Toyokuni S, Kita T

CIRCULATION 110 巻 ( 17 ) 頁： 514 - 515 2004年10月

Novel mechanism of matrix metalloproteinase inhibitor in the treatment of heart failure:: Direct inhibition of myocardial oxidant stress and NF-κB activation in rats 国際誌

Takenaka, H, Kihara, Y, Iwanaga, Y, Onozawa, Y, Toyokuni, S, Kita, T

CIRCULATION 110 巻 ( 17 ) 頁： 514 - 515 2004年10月

Transgenic mice produced by retroviral transduction of male germ line stem cells in vivo. 国際誌 Open Access

Kanatsu-Shinohara M, Toyokuni S, Shinohara T

Biology of reproduction 71 巻 ( 4 ) 頁： 1202 - 7 2004年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biology of Reproduction

Spermatogonial stem cells are the only stem cells in the postnatal body that can transmit parental genetic information to the offspring, making them an attractive target cell population for animal transgenesis. Although transgenic mice and rats were recently produced by retrovirus transduction of these cells in vitro, with transplantation of the transduced cells into infertile recipients, the difficulty of restoring fertility and preparing recipients using spermatogonial transplantation limits practical application of the technique. In this article, we describe a novel approach for producing transgenic animals by transducing spermatogonial stem cells in vivo using a retrovirus vector. Microinjection of retrovirus into immature seminiferous tubules resulted in the direct transduction of spermatogonial stem cells in situ, and the animals produced transgenic offspring after mating with females. Transgenic mice were produced in C57BL/6, BALB/C, A, and C3H backgrounds, with an average efficiency of 2.8%. The transgene was transmitted stably and expressed in the next generation. The technique overcomes the drawback of the in vitro-transduction approach, and will be useful as a novel method for producing transgenic animals as well as providing a means for analyzing the self-renewal and differentiation processes of spermatogonial stem cells in vivo.

DOI： 10.1095/biolreprod.104.031294

Cyp3A induction aggravates endotoxemic liver injury via reactive oxygen species in male rats 査読有り国際誌

Minamiyama, Y; Takemura, S; Toyokuni, S; Imaoka, S; Funae, Y; Hirohashi, K; Yoshikawa, T; Okada, S

FREE RADICAL BIOLOGY AND MEDICINE 37 巻 ( 5 ) 頁： 703 - 712 2004年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Biology and Medicine

We carried out this experiment to evaluate the relationship between isoforms of cytochrome P450 (P450) and liver injury in lipopolysaccharide (LPS)-induced endotoxemic rats. Male rats were intraperitoneally administered phenobarbital (PB), a P450 inducer, for 3 days, and 1 day later, they were intravenously given LPS. PB significantly increased P450 levels (200% of control levels) and the activities (300-400% of control) of the specific isoforms (CYP), CYP3A2 and CYP2B1, in male rats. Plasma AST and ALT increased slightly more in PB-treated rats than in PB-nontreated (control) rats with LPS treatment. Furthermore, either troleandomycin or ketoconazole, specific CYP3A inhibitors, significantly inhibited LPS-induced liver injury in control and PB-treated male rats. To evaluate the oxidative stress in LPS-treated rats, in situ superoxide radical detection using dihydroethidium (DHE), hydroxy-2-nonenal (HNE)-modified proteins in liver microsomes and 8-hydroxydeoxyguanosine (8-OHdG) in liver nuclei were measured in control and PB-treated rats. DHE signal intensity, levels of HNE-modified proteins, and 8-OHdG increased significantly in PB-treated rats. LPS further increased DHE intensity, HNE-modified proteins, and 8-OHdG levels in normal and PB-treated groups. CYP3A inhibitors also inhibited the increases in these items. Our results indicate that the induction or preservation of CYP isoforms further promotes LPS-induced liver injury through mechanisms related to oxidative stress. In particular, CYP3A2 of P450 isoforms made an important contribution to this LPS-induced liver injury. © 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.freeradbiomed.2004.05.022

Gastric inhibitory polypeptide is the major insulinotropic factor in K-ATP null mice 査読有り国際誌

Tsukiyama K, Yamada Y, Miyawaki K, Hamasaki A, Nagashima K, Hosokawa M, Fujimoto S, Takahashi A, Toyoda K, Toyokuni S, Oiso Y, Seino Y

EUROPEAN JOURNAL OF ENDOCRINOLOGY 151 巻 ( 3 ) 頁： 407 - 412 2004年9月

Gastric inhibitory polypeptide is the major insulinotropic factor in K(ATP) null mice.

Tsukiyama K, Yamada Y, Miyawaki K, Hamasaki A, Nagashima K, Hosokawa M, Fujimoto S, Takahashi A, Toyoda K, Toyokuni S, Oiso Y, Seino Y

European journal of endocrinology 151 巻 ( 3 ) 頁： 407 - 12 2004年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Endocrinology

Objective: ATP-sensitive K+ (KATP) channels in pancreatic β-cells are crucial in the regulation of glucose-induced insulin secretion. Recently, KATP channel-deficient mice were generated by genetic disruption of Kir6.2, the pore-forming component of KATP channels, but the mice still showed a significant insulin response after oral glucose loading in vivo. Gastric inhibitory polypeptide (GIP) is a physiological incretin that stimulates insulin release upon ingestion of nutrients. To determine if GIP is the insulinotropic factor in insulin secretion in KATP channel-deficient mice, we generated double-knockout Kir6.2 and GIP receptor null mice and compared them with Kir6.2 knockout mice. Methods: Double-knockout mice were generated by intercrossing Kir6.2-knockout mice with GIP receptor-knockout mice. An oral glucose tolerance test, insulin tolerance test and batch incubation study of pancreatic islets were performed on double-knockout mice and Kir6.2-knockout mice. Results: Fasting glucose and insulin levels were similar in both groups. After oral glucose loading, blood glucose levels of double-knockout mice became elevated compared with Kir6.2-knockout mice, especially at 15min (345±10mg/dl vs 294±20mg/dl, P<0.05 and 30min (453±20 mg/dl vs 381 ± 26 mg/dl, P < 0.05). The insulin response was almost completely lost in double-knockout mice, although insulin secretion from isolated islets was stimulated by another incretin, glucagon-like peptide-1 in the double-knockout mice. Double-knockout mice and Kir6.2-knockout mice were similarly insulin sensitive as assessed by the insulin tolerance test. Conclusion: GIP is the major insulinotropic factor in the secretion of insulin in response to glucose load in KATP channel-deficient mice. © 2004 Society of the European Journal of Endocrinology.

DOI： 10.1530/eje.0.1510407

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PubMed

Gastric inhibitory polypeptide is the major insulinotropic factor in K(ATP) null mice. 査読有り国際誌

Katsushi Tsukiyama, Yuichiro Yamada, Kazumasa Miyawaki, Akihiro Hamasaki, Kazuaki Nagashima, Masaya Hosokawa, Shimpei Fujimoto, Akira Takahashi, Kentaro Toyoda, Shinya Toyokuni, Yutaka Oiso, Yutaka Seino

European journal of endocrinology 151 巻 ( 3 ) 頁： 407 - 12 2004年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells are crucial in the regulation of glucose-induced insulin secretion. Recently, K(ATP) channel-deficient mice were generated by genetic disruption of Kir6.2, the pore-forming component of K(ATP) channels, but the mice still showed a significant insulin response after oral glucose loading in vivo. Gastric inhibitory polypeptide (GIP) is a physiological incretin that stimulates insulin release upon ingestion of nutrients. To determine if GIP is the insulinotropic factor in insulin secretion in K(ATP) channel-deficient mice, we generated double-knockout Kir6.2 and GIP receptor null mice and compared them with Kir6.2 knockout mice. METHODS: Double-knockout mice were generated by intercrossing Kir6.2-knockout mice with GIP receptor-knockout mice. An oral glucose tolerance test, insulin tolerance test and batch incubation study of pancreatic islets were performed on double-knockout mice and Kir6.2-knockout mice. RESULTS: Fasting glucose and insulin levels were similar in both groups. After oral glucose loading, blood glucose levels of double-knockout mice became elevated compared with Kir6.2-knockout mice, especially at 15 min (345+/-10 mg/dl vs 294+/-20 mg/dl, P<0.05) and 30 min (453+/-20 mg/dl vs 381+/-26 mg/dl, P<0.05). The insulin response was almost completely lost in double-knockout mice, although insulin secretion from isolated islets was stimulated by another incretin, glucagon-like peptide-1 in the double-knockout mice. Double-knockout mice and Kir6.2-knockout mice were similarly insulin sensitive as assessed by the insulin tolerance test. CONCLUSION: GIP is the major insulinotropic factor in the secretion of insulin in response to glucose load in K(ATP) channel-deficient mice.

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Prevention of myocardial reperfusion injury by poly(ADP-ribose) synthetase inhibitor, 3-aminobenzamide, in cardioplegic solution: in vitro study of isolated rat heart model. 国際誌 Open Access

Yamazaki K, Miwa S, Ueda K, Tanaka S, Toyokuni S, Unimonh O, Nishimura K, Komeda M

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 26 巻 ( 2 ) 頁： 270 - 5 2004年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Cardio-thoracic Surgery

Objective: Cardioplegic arrest remains the method of choice for myocardial protection in cardiac surgery. Poly(adenosine 5′-diphosphate-ribose) synthetase (PARS) inhibitor has been suggested to attenuate the ischemia-reperfusion injury in myocardial infarction by preventing energy depletion associated with oxidative stress. We investigated the efficacy of a cardioplegic solution containing a PARS inhibitor, 3-aminobenzamide (3-AB), for myocardial protection against ischemia-reperfusion injury caused by cardioplegic arrest. Methods: Isolated hearts were set on a Langendorff apparatus and perfused. The hearts were arrested for 90 min with a cardioplegic solution given at 30-min intervals and then reperfused for 20 min. The hearts of rat in the 3-AB(-) group (n=8) were perfused with a standard cardioplegic solution and terminal warm cardoplegia, whereas the 3-AB(+) group (n=8) received these solutions supplemented with 3-AB (100 μM). Left ventricular function and release of cardiac enzymes were monitored before and after cardioplegic arrest. After reperfusion, NAD+ (nicotinamide-adenine dinucleotide) levels were assessed, and the tissues were examined immunohistochemically for oxidative stress and apoptosis. Results: During reperfusion, the 3-AB(+) group showed significantly higher (P=0.005) dp/dt and lower creatine phosphokinase (CPK) level and glucotamic-oxaloacetic transaminase (GOT) in the effluent (CPK; P=0.003, GOT; P<0.001). The cardiomyocytes of the 3-AB(+) group also preserved a higher NAD+ level (P<0.001). Immunohistochemical study of oxidative stress revealed a lesser extent (P=0.007) of nuclear staining and a lower fraction of apoptosis in the 3-AB(+) group. Conclusion: Cardioplegic solution supplemented with 3-AB provides efficient myocardial protection in cardioplegic ischemic reperfusion by suppressing oxidative stress and overactivation of PARS. © 2004 Published by Elsevier B.V.

DOI： 10.1016/j.ejcts.2004.04.044

Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. 査読有り国際誌 Open Access

Satou Y, Nosaka K, Koya Y, Yasunaga JI, Toyokuni S, Matsuoka M

Leukemia 18 巻 ( 8 ) 頁： 1357 - 63 2004年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Leukemia

Adult T-cell leukemia (ATL) is a fatal neoplasm derived from CD4-positive T-lymphocytes, and regardless of intensive chemotherapy, its mean survival time is less than 1 year. Nuclear factor-κB (NF-κB) activation was reported in HTLV-I associated cells, and has been implicated in oncogenesis and resistance to anticancer agents and apoptosis. We studied the effect of a proteasome inhibitor, bortezomib (formerly known as PS-341), on ATL cells in vitro and in vivo. Bortezomib could inhibit the degradation Of IκBα in ATL cells, resulting in suppression of NF-κB and induction of cell death in ATL cells in vitro. Susceptibilities to bortezomib were well correlated with NF-κB activation, suggesting that suppression of the NF-κB pathway was implicated in the cell death induced by bortezomib. Although the majority of the cell death was apoptosis, necrotic cell death was observed in the presence of a caspase inhibitor, z-VAD-fmk. When bortezomib was administered into SCID mice bearing tumors, it suppressed tumor growth in vivo, showing that bortezomib was effective against ATL cells in vivo. These studies revealed that bortezomib is highly effective against ATL cells in vitro and in vivo by induction of apoptosis, and its clinical application might improve the prognosis of patients with this fatal disease. © 2004 Nature Publishing Group All rights reserved.

DOI： 10.1038/sj.leu.2403400

その他リンク： http://orcid.org/0000-0002-7939-2080

Regulation of mouse spermatogonial stem cell self-renewing division by the pituitary gland. 査読有り国際誌 Open Access

Kanatsu-Shinohara M, Morimoto T, Toyokuni S, Shinohara T

Biology of reproduction 70 巻 ( 6 ) 頁： 1731 - 7 2004年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biology of Reproduction

Spermatogenesis originates in spermatogonial stem cells, which have the unique mode of replication. It is considered that a single stem cell can produce two stem cells (self-renewing division), one stem and one differentiating (asymmetric division), or two differentiating cells (differentiating division). However, little is known regarding how each type of division is regulated. In this investigation, we focused on the analysis of self-renewing division and examined the effect of the pituitary gland using two models of stem cell self-renewing division. In the first experiment using newborn mice, the administration of GnRH-analogue, which represses the release of gonadotropin, reduced the number of stem cells during postnatal testicular development, suggesting that the pituitary gland enhances stem cell self-renewing division. In the second experiment, however, the number of stem cells increased dramatically in hypophysectomized adult recipients after spermatogonial transplantation. Thus, the pituitary gland affects the self-renewing division of stem cells, but these contradictory results suggest that its role may be different depending on the stage of the testicular development.

DOI： 10.1095/biolreprod.103.025668

PAX6 regulates islet β-cell function

Hamasaki, A; Yamada, Y; Nagashima, K; Fujimoto, S; Ban, N; Toyokuni, S; Kurose, T; Seino, Y

DIABETES 53 巻頁： A394 - A394 2004年6月

Role of reactive oxygen species in skin carcinogenesis

Nishigori C, Hattori Y, Toyokuni S

ANTIOXIDANTS & REDOX SIGNALING 6 巻 ( 3 ) 頁： 561 - 570 2004年6月

Redox control of carcinogenesis and tumor biology

Toyokuni S

ANTIOXIDANTS & REDOX SIGNALING 6 巻 ( 3 ) 頁： 481 - 482 2004年6月

Role of reactive oxygen species in skin carcinogenesis.

Nishigori C, Hattori Y, Toyokuni S

Antioxidants & redox signaling 6 巻 ( 3 ) 頁： 561 - 70 2004年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Antioxidants and Redox Signaling

Reactive oxygen species (ROS) are associated not only with initiation, but also with promotion and progression in the multistage carcinogenesis model. In the present review, we will focus on the involvement of ROS in skin carcinogenesis, especially that induced by ultraviolet (UV) radiation. UV-specific DNA damage has been well studied thus far. However, recent reports have revealed the previously unknown participation of oxidative stress in UV-induced skin carcinogenesis. Indeed, in addition to transition-type mutations at dipyrimidine sites, G:C to T:A transversions, which may be induced by the presence of 8-oxoguanine during DNA replication, are frequently observed in the ras oncogene and p53 tumor suppressor gene in human skin cancers of sun-exposed areas and in UV-induced mouse skin cancers. Recent studies have shown that not only UV-B, but also UV-A is involved in UV-induced carcinogenesis. A wide variety of biological phenomena other than direct influence by UV, such as inflammatory and immunological responses and oxidative modifications of DNA and proteins, appear to play roles in UV-induced skin carcinogenesis. Furthermore, it has become clear that genetic diseases such as xeroderma pigmentosum show deficient repair of oxidatively modified DNA lesions. The involvement of ROS in skin carcinogeneisis caused by arsenic and chemical carcinogens will also be discussed.

DOI： 10.1089/152308604773934314

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PubMed

Redox control of carcinogenesis and tumor biology.

Toyokuni S

Antioxidants & redox signaling 6 巻 ( 3 ) 頁： 481 - 2 2004年6月